A phase I dose-escalation study of a first-in-class HIF1 and HIF2 dual inhibitor R01 in patients with advanced tumors.

e15097 Background: Hypoxia Inducible Factors 1 and 2 (HIFs) are over-activated in nearly all tumors but not in normal tissues, making them attractive targets for cancer therapy. However, single inhibition of either HIF pathway alone has proven ineffective in repressing tumor growth. R01 is an orally-administered first-in-class dual inhibitor of HIFs, with a broad spectrum of anticancer activity in preclinical models. Methods: This first-in-human, open-label, phase 1 study evaluated the safety and tolerability pharmacokinetics (PK), recommended phase 2 dose (RP2D) and efficacy of R01. A dose-escalation trial using a 3+3 design was conducted involving 22 eligible patients with locally advanced (n = 3) or metastatic solid tumors (n = 19) who had relapsed or were refractory to standard treatments. Cancer types included non-small cell lung cancer (n = 7), colorectal cancer (n = 6), nasopharyngeal cancer (n = 2), and others (n = 7). R01 was given orally until disease progression (PD) or intolerance occurred, and dose escalated from 40 to 480 mg/day. Results: This was an interim report (Data cutoff: Dec 25, 2024). 22 pts were evaluable for toxicity. Treatment-related adverse events (TRAEs) occurred in 36.3% [8/22] of pts (G3 in 13.6% [3/22]). Most frequent TRAEs ( > 10%) were anemia (27.3%), which was reversible and only occurred among patients with prior anemia history. No other > G2 TRAEs were observed. No dose-limiting toxicities (DLTs) and drug-related deaths were observed; the maximum tolerated dose (MTD) was not reached. The RP2D was 160 mg three times daily(TID). Leucopenia, lymphopenia, thrombocytopenia, and fatigue never occurred during this study in any patient. 18 pts were evaluable for efficacy and 10 pts achieved stable disease (SD), including 3 of 3 with squamous cell lung cancer. At clinically active doses (≥160 mg/d), 10 of 15 (66.7%) patients achieved SD. Particularly notable, after receiving R01 (240 mg/day), a very heavily pretreated ( > 9 therapies) colorectal cancer patient with lung metastases harboring concurrent Kras G12V/p53 mutations obtained notably longer PFS ( > 7.5 months) than those who received any FDA-approved drug for colorectal cancer. 1pt has PDL1 (-) squamous cell lung cancer and continues on study after over 8 months with SD, and 1 pt with nasopharyngeal cancer, refractory to standard treatment achieved SD for 6 months while receiving low-dose R01 (160 mg/day), both with over a 10% shrinkage in tumor size. Mean area under the curve (AUC) and peak plasma concentration (Cmax) increased proportionally with dose escalation from 40 mg to 360 mg daily. Mean half life (T 1/2 ) was about 3 hours, with minimal accumulation of R01. Conclusions: R01 has shown an extremely excellent safety profile, favorable pharmacokinetics, and very encouraging activity across a broad range of tumor types. Recruitment into the phase-2 part of the study is ongoing. Clinical trial information: ChiCTR2500095101 .